1. Field of invention
The invention relates in general to pharmaceutical compositions containing 1-oleylazacycloheptan-2-one in the function of human or animal epithelial membrane permeability enhancer. Furthermore the invention encompasses the use of above pharmaceutical compositions for the treatment of for instance inflammation as well as the compound per se.
2. Background of the prior art
One of the epithelial membranes of interest is the skin. More in particular the skin is frequently used as a portal of entry into the body for two classes of physiologically active agents: (I) systemically active agents, (II) locally active agents. For an increasing number of systemically active agents, delivery through the skin is favorable, since absorption kinetics can be controlled, and various side effects (such as hepatic first-pass metabolism) avoided.
For locally active agents, such as anti-inflammatory drugs, the skin is both the portal of entry and the target organ.
Generally, the greatest problem in applying physiologically active agents topically is that the skin is an effective barrier for penetration of such agents. The epidermis of the skin has an exterior layer of dead cells called the "stratum corneum" which is tightly structured, lipid rich and which provides an effective barrier against all kinds of agents whether used alone or in water or oil solution or suspension. However, once a physiologically active agent has penetrated the stratum corneum it can readily pass through the basal layer of the epidermis and into the dermis.
In the prior art many vehicle compositions are disclosed containing 1-substituted azacycloheptan-2-ones useful in enhancing penetration of the skin by physiologically active agents.
In British patent specification 1,553,309 a large number of 1-al-kylazacycloheptan-2-ones, in particular 1-n-dodecylazacycloheptan-2-one are disclosed. As indicated on page 1 of this British patent these compounds are found to be useful as vehicles for delivering physiologically active agents through body membranes such as the skin and for retaining these agents in body tissues. However, no details concerning the possible mode(s) of action of these 1-C.sub.1-18 alkylazacycloheptan-2-ones are reported in this patent.
U.S. Pat. No. 3,989,816 discloses a method for enhancing the penetration of physiologically active agents through human and animal membranes e.g. the skin by administering to a human or animal membrane a composition comprising an effective amount of the active agent and a suitable amount of an 1-alkyl-azacycloheptan-2-one, the alkyl substituent having the formula --(CH.sub.2)n--R, wherein R is selected from the group consisting of alkyl moieties having 1-18 carbon atoms and aryl groups, and n is 0 or a positive integer from 1-10. Preferably the alkyl substituent has 1-12 carbon atoms. However, the penetration enhancing properties of these compounds are considered inadequate.
Further U.S. Pat. No. 4,310,525 relates to the application of an effective amount of 1-dodecyl-azacycloheptan-2-one as the sole anti-inflammatory agent for treating inflammation in humans and animals. The active compound is used in the form of a composition applied topically on the human or animal skin. The concentration of 1-dodecylazacycloheptan-2-one in the -composition may vary from about 10 to 100% and preferably from about 42 to 80% by weight. According to this U.S. Pat. No. 4,310,525 the compound 1-dode-cyl-azacycloheptan-2-one per se is not used as penetration enhancer for physiologically active agents, but is, apparently, as such capable of temporarily reducing the signs and symptoms of inflammation.
EP-A-0 129 284 relates to topical pharmaceutical compositions containing a physiologically active agent and a binary combination of 1-dodecyl-azacycloheptan-2-one on the one hand and a specific C.sub.3 -C.sub.4 -diol or a 1-substituted azacycloalkyl-2-one on the other hand as penetration enhancing agents. However, the use of a mixture of specific membrane-penetration enhancing agents at specific ratio's is considered undesirable whereas nothing is disclosed about the possible toxic properties of these enhancer mixtures.
EP-A-0 251 425 discloses an article for the administration of physiologically active substances comprising a plasticized polyvinylchloride layer containing from about 20 to about 70% by wt. of a polyvinyl-chloride resin from about 20 to about 70 % of a plasticizer and from about 0.5 to 35% of the physiologically active substance. The plasticizer may be 1-dodecyl-azacycloheptan-2-one which in fact also acts as a membrane penetration enhancer for the physiologically active compound through the stratum corneum.